CN105073742B - Flap调节剂 - Google Patents
Flap调节剂 Download PDFInfo
- Publication number
- CN105073742B CN105073742B CN201480019599.1A CN201480019599A CN105073742B CN 105073742 B CN105073742 B CN 105073742B CN 201480019599 A CN201480019599 A CN 201480019599A CN 105073742 B CN105073742 B CN 105073742B
- Authority
- CN
- China
- Prior art keywords
- cyclobutyl
- bases
- amine
- fluoro
- pyrazine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
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- 238000000034 method Methods 0.000 claims abstract description 90
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 25
- 239000002585 base Substances 0.000 claims description 728
- XFTQRUTUGRCSGO-UHFFFAOYSA-N pyrazin-2-amine Chemical compound NC1=CN=CC=N1 XFTQRUTUGRCSGO-UHFFFAOYSA-N 0.000 claims description 560
- -1 heterocyclic radical Chemical class 0.000 claims description 470
- 239000000203 mixture Substances 0.000 claims description 173
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 160
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 104
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 101
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 101
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 92
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 82
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 70
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 61
- 201000010099 disease Diseases 0.000 claims description 55
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- 102100022278 Arachidonate 5-lipoxygenase-activating protein Human genes 0.000 claims description 49
- LJXQPZWIHJMPQQ-UHFFFAOYSA-N pyrimidin-2-amine Chemical compound NC1=NC=CC=N1 LJXQPZWIHJMPQQ-UHFFFAOYSA-N 0.000 claims description 48
- 101710187011 Arachidonate 5-lipoxygenase-activating protein Proteins 0.000 claims description 46
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 42
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- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 24
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- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 23
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 23
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- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims description 21
- 239000000126 substance Substances 0.000 claims description 21
- BHHMPZQRVWVAAR-UHFFFAOYSA-N 7-bromo-8-methylpyrido[2,3-b]pyrazine Chemical compound C1=CN=C2C(C)=C(Br)C=NC2=N1 BHHMPZQRVWVAAR-UHFFFAOYSA-N 0.000 claims description 20
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- 235000010233 benzoic acid Nutrition 0.000 claims description 19
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 19
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- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 17
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- 125000001072 heteroaryl group Chemical group 0.000 claims description 16
- RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical class C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 14
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- LETVJWLLIMJADE-UHFFFAOYSA-N pyridazin-3-amine Chemical compound NC1=CC=CN=N1 LETVJWLLIMJADE-UHFFFAOYSA-N 0.000 claims description 13
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 12
- 239000003513 alkali Substances 0.000 claims description 12
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 12
- RSJKGSCJYJTIGS-UHFFFAOYSA-N undecane Chemical compound CCCCCCCCCCC RSJKGSCJYJTIGS-UHFFFAOYSA-N 0.000 claims description 12
- 229910021529 ammonia Inorganic materials 0.000 claims description 11
- 230000000694 effects Effects 0.000 claims description 11
- 208000023504 respiratory system disease Diseases 0.000 claims description 11
- AYDQIZKZTQHYIY-UHFFFAOYSA-N OC(=O)C1(C)CC(C(O)=O)=CC=C1 Chemical compound OC(=O)C1(C)CC(C(O)=O)=CC=C1 AYDQIZKZTQHYIY-UHFFFAOYSA-N 0.000 claims description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 10
- 201000011510 cancer Diseases 0.000 claims description 10
- 230000008859 change Effects 0.000 claims description 10
- PMSVVUSIPKHUMT-UHFFFAOYSA-N cyanopyrazine Chemical compound N#CC1=CN=CC=N1 PMSVVUSIPKHUMT-UHFFFAOYSA-N 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Chemical compound C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 claims description 9
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- 208000010668 atopic eczema Diseases 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 9
- 238000006467 substitution reaction Methods 0.000 claims description 9
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims description 9
- FFNVQNRYTPFDDP-UHFFFAOYSA-N 2-cyanopyridine Chemical compound N#CC1=CC=CC=N1 FFNVQNRYTPFDDP-UHFFFAOYSA-N 0.000 claims description 8
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- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 8
- 150000003053 piperidines Chemical class 0.000 claims description 8
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims description 7
- 206010008190 Cerebrovascular accident Diseases 0.000 claims description 7
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- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
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- 208000010125 myocardial infarction Diseases 0.000 claims description 7
- ZENKESXKWBIZCV-UHFFFAOYSA-N 2,2,4,4-tetrafluoro-1,3-benzodioxin-6-amine Chemical group O1C(F)(F)OC(F)(F)C2=CC(N)=CC=C21 ZENKESXKWBIZCV-UHFFFAOYSA-N 0.000 claims description 6
- LVILGAOSPDLNRM-UHFFFAOYSA-N 4-methylpyrimidine Chemical compound CC1=CC=NC=N1 LVILGAOSPDLNRM-UHFFFAOYSA-N 0.000 claims description 6
- MKLQPIYLZMLAER-UHFFFAOYSA-N 4-phenylpyrimidine Chemical compound C1=CC=CC=C1C1=CC=NC=N1 MKLQPIYLZMLAER-UHFFFAOYSA-N 0.000 claims description 6
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 6
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- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims description 6
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- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 6
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- 125000004494 ethyl ester group Chemical group 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
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- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 6
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 claims description 6
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- 150000003230 pyrimidines Chemical class 0.000 claims description 6
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- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 claims description 5
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
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- MWLSOWXNZPKENC-SSDOTTSWSA-N zileuton Chemical compound C1=CC=C2SC([C@H](N(O)C(N)=O)C)=CC2=C1 MWLSOWXNZPKENC-SSDOTTSWSA-N 0.000 description 1
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Classifications
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US9745328B2 (en) | 2013-02-04 | 2017-08-29 | Janssen Pharmaceutica Nv | Flap modulators |
US9718816B2 (en) | 2013-03-15 | 2017-08-01 | Epizyme, Inc. | 1-phenoxy-3-(alkylamino)-propan-2-ol derivatives as CARM1 inhibitors and uses thereof |
BR112015022787A2 (pt) | 2013-03-15 | 2017-11-07 | Epizyme Inc | compostos, composições farmacêuticas, kit ou artigo farmacêutico embalado, e método de tratamento de um distúrbio mediado por carm1 |
US9346802B2 (en) | 2013-03-15 | 2016-05-24 | Epizyme, Inc. | CARM1 inhibitors and uses thereof |
WO2016044641A2 (en) * | 2014-09-17 | 2016-03-24 | Epizyme, Inc. | Carm1 inhibitors and uses thereof |
CN104961642A (zh) * | 2015-06-26 | 2015-10-07 | 华中药业股份有限公司 | 一种合成普萘洛尔的新方法 |
CN108026079B (zh) | 2015-09-24 | 2020-09-22 | 株式会社Lg化学 | 化合物和包含其的有机发光器件 |
CN108329330B (zh) * | 2017-01-20 | 2021-05-04 | 复旦大学 | 2-苄氧苯基噁唑并吡啶类化合物及其药物用途 |
KR20210116549A (ko) | 2019-01-18 | 2021-09-27 | 아스트라제네카 아베 | Pcsk9 억제제 및 이의 이용 방법 |
JP7486382B2 (ja) | 2020-08-31 | 2024-05-17 | 東京エレクトロン株式会社 | 搬送装置および搬送方法 |
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- 2014-01-31 KR KR1020157024124A patent/KR20160004258A/ko not_active Application Discontinuation
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CN105073742A (zh) | 2015-11-18 |
EA030404B1 (ru) | 2018-07-31 |
MX2015010106A (es) | 2016-01-14 |
AU2017213500A1 (en) | 2017-08-31 |
US10047101B2 (en) | 2018-08-14 |
US20150252008A1 (en) | 2015-09-10 |
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US9732093B2 (en) | 2017-08-15 |
US9073876B2 (en) | 2015-07-07 |
WO2014121040A8 (en) | 2015-02-12 |
JP6328145B2 (ja) | 2018-05-23 |
MX364069B (es) | 2019-04-10 |
US20140221310A1 (en) | 2014-08-07 |
JP2016514089A (ja) | 2016-05-19 |
US20150368270A1 (en) | 2015-12-24 |
EP2951169A1 (en) | 2015-12-09 |
EP2951169B1 (en) | 2019-08-28 |
AU2014212193B2 (en) | 2017-06-15 |
KR20160004258A (ko) | 2016-01-12 |
WO2014121040A1 (en) | 2014-08-07 |
TWI644899B (zh) | 2018-12-21 |
CA2899904A1 (en) | 2014-08-07 |
AU2017213500B2 (en) | 2019-02-28 |
US20170327514A1 (en) | 2017-11-16 |
TW201444799A (zh) | 2014-12-01 |
UY35305A (es) | 2014-08-29 |
HK1217489A1 (zh) | 2017-01-13 |
EA201591451A1 (ru) | 2015-12-30 |
BR112015018504A2 (pt) | 2017-07-18 |
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